Previous work, in large part by this PPG, has shown that chronic exposure to cocaine or other drugs of abuse increases the transcriptional activity of deltaFosB and CREB in the nucleus accumbens (NAc). Our work suggests further that deltaFosB and CREB up-regulation may contribute differently to addiction-related changes in cocaine self-administration as well as to the propensity for relapse in withdrawal. Studies conducted in the Behavioral Core have found that two downstream targets regulated by deltaFosB and CREB, CDK-5 and BDNF, also regulate cocaine sensitivity in locomotion and place preference tests. Similarly, chronic cocaine increases RGS9-2 levels in NAc, an upstream regulator of D2 dopamine receptor signaling, an effect which reduces sensitivity to cocaine. The goal of Project 4 is to study the functional contribution of cocaine-induced up-regulation of these proteins to addiction-related changes in self-administration and cocaine seeking in withdrawal. It will also coordinate the application of intracranial self-stimulation and conditioned reward paradigms, available in the Behavioral Core, to these same proteins. The first major aim will compare up-regulation of deltaFosB, CREB, CDK-5, BDNF, and RGS-9 in NAc core and shell subregions with individual differences in cocaine intake in self-administering animals. Studies also will track protein up-regulation from early to late withdrawal times, and will compare changes with non-reinforced yoked animals receiving identical amounts of cocaine. A second major aim will utilize transgenic and pharmacological approaches in rats and mice to modulate deltaFosB, CREB, CDK-5, BDNF, and RGS-9 levels specifically in NAc core and shell subregions during cocaine self-administration tests. These studies will investigate the direct role of target protein overexpression in regulating discrete aspects of self-administration, including acquisition and maintenance of cocaine self-administration on fixed and progressive ratio schedules of reinforcement. Complementary analysis will utilize expression of dominant negative mutants and region-specific knockouts of floxed genes in NAc core and shell. A final aim will utilize similar transgenic and pharmacological strategies to study the direct effects of target protein overexpression in NAc core and shell on relapse to cocaine seeking in withdrawal, using an extinction/reinstatement procedure. Experiments also will study the effects of target protein overexpression on incentive learning during self-administration, which may indirectly facilitate subsequent cocaine-seeking, even after target protein levels decline to normal in Iong-tem abstinence. Together, these studies combine state of the art transgenic technology with highly relevant behavioral models to investigate the contribution of specific cocaine-induced neuroadaptations in the NAc to discrete behavioral changes that underlie the addicted phenotype.